Peak oxygen uptake in combination with ventilatory efficiency improve risk stratification in major abdominal surgery

Abstract This pilot study aimed to evaluate if peak VO2 and ventilatory efficiency in combination would improve preoperative risk stratification beyond only relying on peak VO2. This was a single‐center retrospective cohort study including all patients who underwent cardiopulmonary exercise testing (CPET) as part of preoperative risk evaluation before major upper abdominal surgery during years 2008–2021. The primary outcome was any major cardiopulmonary complication during hospitalization. Forty‐nine patients had a preoperative CPET before decision to pursue to surgery (cancer in esophagus [n = 18], stomach [6], pancreas [16], or liver [9]). Twenty‐five were selected for operation. Patients who suffered any major cardiopulmonary complication had lower ventilatory efficiency (i.e., higher VE/VCO2 slope, 37.3 vs. 29.7, p = 0.031) compared to those without complications. In patients with a low aerobic capacity (i.e., peak VO2 < 20 mL/kg/min) and a VE/VCO2 slope ≥ 39, 80% developed a major cardiopulmonary complication. In this pilot study of patients with preoperative CPET before major upper abdominal surgery, patients who experienced a major cardiopulmonary complication had significantly lower ventilatory efficiency compared to those who did not. A low aerobic capacity in combination with low ventilatory efficiency was associated with a very high risk (80%) of having a major cardiopulmonary complication.

assessment by the preoperative physician has a low sensitivity in identifying patients with low functional capacity and is an insufficient predictor of postoperative morbidity and mortality (Wijeysundera et al., 2018).
Cardiopulmonary exercise testing (CPET) is the gold standard for objective assessment of exercise tolerance and overall cardiopulmonary function (Levett et al., 2018).Studies support the use of CPET for preoperative risk prediction in esophageal/gastric surgery (Benington et al., 2019;Jack et al., 2014), hepatobiliary surgery (Snowden et al., 2010), and pancreatic surgery (Ausania et al., 2012).
Historically, in abdominal surgery, most studies have used either maximal aerobic capacity (peak VO 2 ) with a threshold of 14 mL/kg/min and/or oxygen uptake (VO 2 ) at the anaerobic threshold (AT) with a threshold of 11 mL/ kg/min to identify patients with a low functional capacity (Wijeysundera et al., 2018).However, advances in CPET methodology and subsequent research have allowed for identification of other measures of relevance for preoperative risk assessment.In particular, measurement of ventilatory parameters such as the slope of the increase in minute ventilation in relation to carbon dioxide elimination, VE/VCO 2 slope (Sun et al., 2002).During the last decade, studies have shown that VE/VCO 2 slope may be a stronger marker for postoperative complications and mortality after lung resection compared to peak VO 2 (Brunelli et al., 2012).CPET has a pivotal role in preoperative guidelines before lung cancer surgery (Brunelli et al., 2013) and incorporation of both peak VO 2 and ventilatory efficiency in an algorithm to improve risk stratification in lung cancer resection has been proposed (Salati & Brunelli, 2016) and recently validated (Kristenson et al., 2022).This approach has also been suggested for preoperative risk stratification for patients evaluated for abdominal surgery (Sivakumar et al., 2022) but this has to our knowledge not been evaluated.
Therefore, the purpose of this pilot study was to evaluate if stratification of patients' functional capacity using a combination of peak VO 2 and ventilatory efficiency could improve preoperative risk assessment in major upper abdominal surgery.

| Participants
The study was designed as a single-center retrospective pilot study including all patients who underwent CPET as part of preoperative risk evaluation before major upper abdominal surgery (esophagus, stomach, pancreas, and liver) at Linköping University Hospital in Sweden in 2008-2021 (Table 2).Ethical permission was granted (DNr 2021-05603-01) and written informed consent was waived by the ethics committee.
Gas exchange and ventilatory variables were measured breath by breath (Jaeger Oxycon Pro or Vyntus CPX; Viasys Healthcare).The system was calibrated before each CPET.Oxygen uptake (VO 2 ), carbon dioxide elimination (VCO 2 ), and ventilation (VE) were presented as 10-s means, excluding the breaths with the highest and lowest values.Peak VO 2 was defined as the average of the two highest consecutive 10-s mean VO 2 intervals at or close to the end of the exercise and was presented as absolute values (mL/ min) as well as relative values (mL/kg/min and percent of predicted [% predicted]) (Gläser et al., 2010).Maximum achieved workload was presented as peak power (measured in Watt) as well as % predicted peak power (Gläser et al., 2013).
To obtain ventilatory variables (VE/VCO 2 slope and the nadir of the ventilatory equivalent of carbon dioxide [EqCO 2 ]), automated slopes using a commercial software (Sentry Suite 3.10; CareFusion GmbH) were used, and these were manually adjusted if deemed necessary by the reviewer.VE/VCO 2 slope was defined as the slope of the increase in VE relative to VCO 2 increase during the linear portion of the curve up until the respiratory compensation point.EqCO 2 nadir was defined as the lowest (i.e., nadir) value of VE/VCO 2 during exercise.The VO2 at the anaerobic threshold (AT) was determined manually.We used a combination of the V-slope method (1st deflection) and evaluation of the ventilatory equivalents of VO 2 and VCO 2 , where the AT was defined as where VE/VO 2 started to increase before an increase in VE/VCO 2 (Levett et al., 2018).
First, patients were grouped based on previously suggested thresholds into either a low or high-risk group, according to peak VO 2 (low risk: ≥14, high risk: <14), VO 2 at AT (low risk: ≥11, high risk: <11), and VE/VCO 2 slope (low risk: <39, high risk: ≥39).Second, patients were grouped into three risk groups applying a joint assessment of peak VO 2 and VE/VCO 2 slope as Group 1 (low risk): peak VO 2 ≥ 20 mL/kg/min, Group 2 (intermediate risk): peak VO 2 < 20 mL/kg/min and VE/VCO 2 slope < 39, and Group 3 (high risk): peak VO 2 < 20 mL/kg/min and VE/ VCO 2 slope ≥ 39.Patients' comorbidities (coronary artery disease, current treatment for heart failure, current treatment for arrythmia, valvular disease, current treatment for hypertension, previous cerebrovascular insult, chronic obstructive pulmonary disease, chronic kidney failure, or diabetes mellitus) were determined by retrospective journal evaluation and followed international recommendations for use of terminology (Fernandez et al., 2015).

| Outcome definitions
The primary outcome was any major cardiopulmonary complication following surgery from admittance to discharge, further defined in Table 1.
Secondary outcomes were Clavien-Dindo complications > grade 2 (complications requiring surgical, endoscopic or radiological intervention with or without general anesthesia, life-threatening complications that require intensive care or death of the patient; Dindo et al., 2004), length of hospital stay, and 90 day mortality.

| Statistical analysis
Statistical analysis was performed using SPSS 27.0.0.0 (IBM-SPSS Inc.).Due to the low number of observations, non-parametrical statistics were used.Median values were presented with corresponding interquartile range (IQR) and compared with the independent-samples Mann-Whitney U test and frequencies were compared with Fischer's exact test.All tests were two-sided, and the significance level was set at p < 0.05.

| RESULTS
In total, 49 patients were included, as they had performed a preoperative CPET before the decision regarding if the patient would pursue to major upper abdominal surgery or not (Figure 1).The median age was 73 years (range 43-88 years, IQR 68-79), and 74% were men (n = 36).Patients were included due to cancer in the esophagus (n = 18), stomach (n = 6), pancreas (n = 16), or liver (n = 9).
No statistically significant differences were found in median age (73.0 vs. 73.5, p = 0.67) or in presence of comorbidities between patients selected for operation compared to the non-operated group (Figure 1 and Appendix 1).However, in general, patients not selected for operation  had less favorable CPET data including significantly lower values of peak power and peak VO 2 and higher VE/VCO 2 slope (Appendix 2).

| CPET in patients with versus without complications
In total, the frequency of major cardiopulmonary complications or a complication, according to Clavien-Dindo, was 32% (N = 8) and 48% (N = 12), respectively.No patient died within 90 days after surgery.The median length of stay was 11 days (IQR 8-22).
No differences were found in presence of comorbidities between patients who suffered a major cardiopulmonary complication compared to those who did not (Table 2).Also, when comparing the median values of preoperative CPET measures, no differences were found in peak power, peak VO 2 , or VO 2 at AT for patients who suffered a major cardiopulmonary complication compared to those who did not.In contrast, higher (less favorable) values of VE/VCO 2 slope and EqCO 2 nadir were present in patients who suffered a major cardiopulmonary complication (Table 3).When analyzing patients who did or did not suffer a complication > grade 2 according to the Clavien-Dindo classification, lower (less favorable) values were found for % predicted peak power and % predicted peak VO 2 in patients who experienced a complication (Table 4).

| Risk stratification
There were statistically non-significant trends that patients with low peak VO 2 or VO 2 at AT or high VE/VCO 2 slope values (defined by previously suggested thresholds) had an increased frequency of complications (Figure 2).However, when using a combined stratification by peak VO 2 and VE/VCO 2 slope, patients with peak VO 2 < 20 mL/ kg/min and VE/VCO 2 slope ≥ 39 (group 3, higher risk) had a statistically significant higher rate of major cardiopulmonary complications and longer length of stay compared to the other risk groups (Figure 3).

| DISCUSSION
In this pilot study of patients who performed CPET before major upper abdominal surgery, we found that patients who suffered a major cardiopulmonary complication had significantly higher (less favorable) values of ventilatory efficiency compared to those who did not sustain a complication.Importantly, we found that by using a combination of low aerobic capacity (peak VO 2 < 20 mL/kg/min) and ventilatory efficiency (VE/ VCO 2 -slope ≥ 39), we were able to identify a group of patients with a particularly high frequency of complications (80%).
Of note, we did not find any significant differences in age or in prevalence of comorbidities in patients selected versus those not selected for surgery.However, patients not selected for surgery were found to have a lower functional capacity, reflected by less favorable results on multiple CPET measures (lower aerobic capacity, ventilatory efficiency as well as anaerobic threshold).When analyzing the risk of postoperative cardiopulmonary complications, again, no differences were found in prevalence of comorbidities between patients who suffered a complication compared to those who did not.However, when comparing the median values of preoperative CPET measures, higher (less favorable) values of VE/VCO 2 slope and EqCO 2 nadir were present in patients who suffered a major cardiopulmonary complication.Interestingly, no differences were found in the more traditional measures peak power, peak VO 2 , or VO 2 at AT for patients who suffered a major cardiopulmonary complication compared to those who did not.These results harmonize with the results from a large multicenter study where the thresholds peak VO 2 14 mL/kg/min and VO 2 at AT 11 mL/kg/ F I G U R E 1 Flowchart of study.
min were not significantly related to an increased risk for the primary outcome (death or myocardial infarction within 30 days after surgery; Wijeysundera et al., 2018).This stresses the importance in using relevant measures and thresholds in preoperative CPET studies.
Interestingly, the strongest risk prediction was found when combining the two measures peak VO 2 and VE/ VCO 2 -slope.This has been evaluated with promising results in thoracic surgery (Kristenson et al., 2022), but this is, to our knowledge, the first study adopting this T A B L E 2 Distribution of gender, comorbidities, and anthropometrics for patients with or without postoperative major cardiopulmonary complications.approach in risk stratifications studies within major abdominal surgery.

| Ventilatory efficiency
Ideally, in the lung, there is a perfect match between perfusion and ventilation.When a mismatch occurs, gas exchange is impaired, and a greater ventilation is requiring for a given output of CO 2 .This ventilatory inefficiency (most often due to increased dead space ventilation) is reflected as an increase in VE/VCO 2 slope measured during CPET (Sun et al., 2002).For example, a VE/VCO 2 slope value of 39 means that a patient needs to exhale 39 liters of air to eliminate 1 liter of CO 2 .VE/VCO 2 slope has in recent decades emerged as a tool to assess both the presence and severity of heart or lung disease (Medinger et al., 2001;Wasserman et al., 1996).VE/VCO 2 slope determination was first used by cardiologists evaluating patients with heart failure (Sun F I G U R E 2 Proportion of patients who suffered or did not suffer a major cardiopulmonary complication after surgery stratified by traditional thresholds for measures from the preoperative cardiopulmonary exercise test.Frequencies of complications were compared with Fischer's exact test.et al., 2002).Therefore, most studies using CPET for preoperative risk stratification refer to thresholds of VE/ VCO 2 slope generated from historical data in heart failure patients (Chua et al., 1997;Corrà et al., 2002), most often using a cutoff of 35 to identify high-risk patients (Brunelli et al., 2012;Shafiek et al., 2016).Recent studies in major abdominal surgery have identified patients with a VE/VCO 2 slope ≥ 39 to have an increased risk of mortality (Wilson et al., 2019) and this threshold was therefore used in the current study.However, as previous authors have suggested, using a single threshold entails a binary approach toward risk assessment, which is problematic in the real, more complex practice of preoperative CPET (Older, 2013;Sivakumar et al., 2022) Therefore, future studies in larger cohorts should strive to identify multiple thresholds that privilege sensitivity and specificity separately (Wilson, 2018).

| Clinical implication
Cardiopulmonary exercise testing has several advantages compared to other means of assessing functional capacity.First, it is possible to determine whether the test was at maximal effort by the patent, which is essential if maximum functional capacity is to be evaluated (such as peak VO 2 ).Second, during CPET, several other variables of importance than maximum capacity can be assessed, such as signs of coronary artery disease, pulmonary comorbidities or ventilatory inefficiency.Third, several of these variables, including VE/VCO 2 slope is measured at submaximal effort and thus does not require a truly maximal test.Future studies should focus on which patients that can be assessed by screening with a more widely available functional test, and which patients benefit from the more comprehensive CPET (Junttila et al., 2022).
After having identified patients at particularly high risk for major cardiopulmonary complications, how can the perioperative physician translate these results to clinical decision-making, ultimately decreasing the risk for the individual patient?First, prehabilitation can be initiated which has been shown to increase functional capacity and lower the risk of complications and mortality for patients undergoing abdominal surgery (Pang et al., 2022;Zarate Rodriguez et al., 2023).Of note, exercise training has been shown to increase not only VO 2 peak, but also ventilatory efficiency (i.e., lowering VE/VCO 2 slope) for patients with heart failure or pulmonary hypertension (Mehani & Abdeen, 2017).It remains to be evaluated whether preoperative risk defined by the combination of peak VO 2 and VE/VCO 2 slope can be affected by prehabilitation in abdominal surgery.Second, if a previously unknown pathology is identified, treatment can be initiated to treat the underlying condition.Third, the data derived from CPET may be used to inform collaborative decision-making and contribute to preoperative risk assessment (Levett et al., 2018).Fourth, high-risk patients that proceed to operation should be assessed and evaluated with caution to identify complications before severe organ failure occurs, a situation that has been called the "failure of rescue" (Ghaferi et al., 2009).Previous studies in colorectal patients have showed that patients preoperatively identified as having an intermediary risk for postoperative complications, the risk was dependent on whether they were treated on a high dependency unit or a standard postoperative ward (Swart et al., 2017).This could in turn speak in favor of having different postoperative care or readiness for complications depending on preoperative risk assessment, where CPET may play an important role.

| Limitations
This is a retrospective, single center pilot study with the aim of exploring if strategies for risk stratification used in thoracic surgery also could be applied in a major upper abdominal surgery cohort.Thus, the total sample is small, and the results should therefore be interpretated with caution.The low power did not allow for any adjustment for other preoperative comorbidities, although there were no statistically significant differences in frequencies of comorbidities between patients who sustained a major cardiopulmonary complication compared to those who did not.The small sample size also precluded stratification by the different types of cancers included, which should be considered in future studies including more patients.

| CONCLUSION
Patients who suffered a major cardiopulmonary complication following major upper abdominal surgery had significantly lower (worse) ventilatory efficiency at preoperative CPET compared to those who did not.Having a low ventilatory efficiency in combination with a low aerobic capacity was associated with a particularly high risk (80%) of suffering a major cardiopulmonary complication.The results from this pilot study calls for validation in larger studies in order to further improve risk assessment in this group of patients.
Definition of study primary outcome.The primary outcome was any major cardiopulmonary complication following surgery until discharge and included either of (a) A major adverse cardiovascular event a • cardiac death • cerebrovascular death • non-fatal cardiac arrest • acute myocardial infarction • congestive heart failure • new cardiac arrhythmia • angina, or stroke (b) A major postoperative pulmonary complication b• Pneumonia (patient has received antibiotics for a suspected respiratory infection and met one or more of the following criteria: new or changed sputum, new or changed lung opacities, fever, white blood cell count <4 × 10 9 /L or > 12 × 10 9 /L)• Moderate respiratory failure (hypoxia requiring continuous positive airway pressure, non-invasive ventilation, highflow nasal cannula or intubation)• Acute respiratory distress syndrome defined by the Berlin criteria c• Atelectasis recurring bronchoscopy (c) Pulmonary embolism (verified with computed tomography pulmonary angiography)a Defined as suggested bySabaté et al. (2011).bModified by the definition ofBriez et al. (2012).

c
Defined as suggested by ARDS Definition Task Force et al. (2012).

F
I G U R E 3 Proportion of patients who suffered or did not suffer a major cardiopulmonary complication after surgery and length of hospital stay for patients from different risk groups based on VO 2 peak (peak oxygen consumption) measured in mL/kg/min, and VE/VCO 2 -slope (ventilatory efficiency) from the preoperative cardiopulmonary exercise test.Median values of length of stay were compared with the Independent-Samples Mann-Whitney U Test and frequencies of complications were compared with Fischer's Exact Test.
Results from preoperative cardiopulmonary exercise testing for patients with or without postoperative major cardiopulmonary complications.
Abbreviations: COPD, Chronic obstructive pulmonary disease; IQR, interquartile range; p, Fischer's exact test.T A B L E 3 Results from preoperative cardiopulmonary exercise test for patients with or without any postoperative complication according to Clavien-Dindo > grade 2. EqCO 2 , ventilatory equivalent for carbon dioxide; ICR, interquartile range; p, Independent-Samples Mann-Whitney U Test for comparison between patients who sustained versus did not sustain a postoperative complication; VO 2 peak, peak oxygen uptake; VCO 2 , carbon dioxide elimination; VE, minute ventilation.
T A B L E 4Abbreviations: